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Aptamers are short oligonucleotides capable of binding specifically to various targets (i.e., small molecules, proteins, and whole cells) which have been introduced in biosensors such as in the electrochemical aptamer-based (E-AB) sensing platform. E-AB sensors are comprised of a redox-reporter-modified aptamer attached to an electrode that undergoes, upon target addition, a binding-induced change in electron transfer rates. To date, E-AB sensors have faced a limitation in the translatability of aptamers into the sensing platform presumably because sequences obtained from Systematic Evolution of Ligands by Exponential Enrichment (SELEX) are typically long (>80 nucleotides) and that obtaining structural information remains time and resource consuming. In response, we explore the utility of aptamer base truncations and in silico docking to improve their translatability into E-AB sensors. Here, we first apply this to the glucose aptamer, which we characterize in solution using NMR methods to guide design and translate truncated variants in E-AB biosensors. We further investigated the applicability of the truncation and computational approaches to four other aptamer systems (vancomycin, cocaine, methotrexate and theophylline) from which we derived functional E-AB sensors. We foresee that our strategy will increase the success rate of translating aptamers into sensing platforms to afford low-cost measurements of molecules directly in undiluted complex matrices., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Philippe Dauphin Ducharme reports financial support was provided by Natural Sciences and Engineering Research Council of Canada. Philippe Dauphin reports financial support was provided by Quebec Research Fund Nature and Technology. If there are other authors, they declare that they have no known Competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A cheap and easy-to-recycle solvent, namely, aqueous NaOH with no additives, was used to dissolve cellulose and make cross-linker-free materials with varying porosity, testing them as drug delivery devices. Cellulose solutions were gelled, coagulated in a nonsolvent (water, ethanol), and dried either using supercritical CO 2 (aerogels) or low-vacuum evaporation (named "xerogels"). Aerogels had densities of around 0.1 g/cm 3 and specific surface areas (SSAs) of 200-400 m 2 /g. A significant influence of the first nonsolvent and drying mode on material properties was recorded: when the first nonsolvent was ethanol and low-vacuum drying was performed from ethanol, aerogel-like xerogels were obtained with densities of around 0.2 g/cm 3 and SSAs of 200-260 m 2 /g. Other conditions (under evaporative drying) resulted in cellulose with much lower porosity and SSA. All materials were evaluated as drug delivery devices in simulated gastrointestinal fluids; theophylline was used as a model drug. Materials of high porosity exhibited shrinking and rapid drug release, whereas denser materials swelled and showed slower release. Two release mechanisms were suggested: diffusion through aqueous media in pores and diffusion through swollen pore walls. The results demonstrate a large spectrum of options for tuning the properties of porous cellulose materials for drug release applications.

This study reports a pH/magnetic dual-responsive hemicellulose-based nanocomposite hydrogel with nearly 100 % carbohydrate polymer-based and biodegradable polymer compositions for drug delivery. We synthesized pure Fe 3 O 4 magnetic nanoparticles (Fe 3 O 4 MNPs) using a co-precipitation method, then engineering xylan hemicellulose (XH), acrylic acid, poly(ethylene glycol) diacrylate, and Fe 3 O 4 to synthesize the pH/magnetic dual-responsive hydrogel (Fe 3 O 4 @XH-Gel), through graft polymerization on XH with in-situ doping Fe 3 O 4 MNPs initiated by the ammonium persulfate/tetramethylethylenediamine redox system. Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance ( 1 H NMR), X-ray diffractometry (XRD), scanning electron microscopy and energy dispersive spectrometer (SEM-EDS), high-resolution transmission electron microscopy (HRTEM), Brunauer-Emmett-Teller (BET), swelling gravimetric analysis, vibrating sample magnetometer (VSM) were employed to analyze the hydrogel's chemical structures, morphologies, pH-responsive behaviors, and magnetic responsiveness characteristics, mechanical and rheological properties, as well as cytotoxicity and biodegradability. The results indicate that the Fe 3 O 4 @XH-Gel exhibited excellent dual responsiveness to pH and magnetism. Furthermore, an emphasis was placed on the in-depth analysis of the pH response mechanism. Finally, we utilized this cutting-edge hydrogel to investigate the controlled-release behavior of two model drugs, Acetylsalicylic acid and Theophylline. The hydrogel demonstrated exceptional controlled release attributes, positioning it as a potential carrier for targeted drug delivery, particularly to the gastrointestinal conditions., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interest. During the preparation of this work the authors used ChatGPT 3.5 in order to improve language and readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A ternary mixture incorporating Hydroxyzine hydrochloride (HYX), Ephedrine hydrochloride (EPH) and Theophylline (THP) frequently prescribed for the treatment of respiratory diseases. Herein, two spectrophotometric methods are designated and applied to resolve these three components in their mixture. Method A is ratio-subtraction combined with derivative spectrophotometry, where THP can be determined directly at its λmax 271 nm (neither HYX or EPH interfere), then for determination of HYX and EPH, the ternary mixture was divided by 22 μg/mL of THP and after subtraction of the plateau region, HYX can be determined directly at its λmax 234.2 nm (absence of EPH intervention). Finally, the third derivative (3D) spectrophotometric approach was utilized to estimate EPH by detecting the peak amplitude at 222 nm with Δλ = 4 and a scaling factor 100. Principal Component Regression (PCR) and Partial Least Squares (PLS), two multivariate calibration approaches, were applied effectively in Method B. This method effectively quantified the mixture under investigation by using the absorption spectra obtained from suitable solutions of the three components in the 210-230 nm region. The calibration models were evaluated using cross-validation with PCR and PLS, producing statistical characteristics that demonstrate the effectiveness of the calibration models. Synthetic and pharmaceutical preparations were also used to conduct external validation. In pharmaceutical formulation, these methods were successfully applied to analyze HYX, EPH, and THP without overlap from formulation's excipients. Moreover, the study's findings were statistically contrasted with those of earlier reported HPLC method. Appraisal approaches were used to determine whether the new spectrophotometric methods had an adverse environmental impact involving the Green Analytical Procedure Index (GAPI) and the AGREE (Analytical Greenness). These evaluations delivered information about the methods' eco-friendliness and sustainability, proving that they are in line with ecologically attributed practices. Furthermore, the Blue Applicability Grade Index (BAGI) was utilized to identify and verify the feasibility and practicality of the suggested approaches., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright: © 2024 AlSalem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The objective of this study was to examine the impact of the physicochemical properties of the loaded drug or excipient, the concentration of Kollidon®SR (KSR), and the mechanical characteristics of KSR compacts on their disintegration times. Using disintegration apparatus, a two-hour constraint was chosen as the process's end point. Lactose-KSR compacts subjected to the highest compression pressure and Microcrystalline cellulose-KSR compacts with KSR concentrations exceeding 30% exhibited disintegration times of less than ten minutes. Likewise, compacts containing Diltiazem HCl-KSR demonstrated brief disintegration times across all tested KSR concentrations and compression pressures. Compacts of Modafinil, Metformin HCl, and Ascorbic acid-KSR displayed disintegration times ranging from fast to moderate, contingent upon the levels of KSR and compression pressure applied. Compacts containing KSR with Aspirin, Salicylic acid, or Ibuprofen did not exhibit significant disintegration even at minimal amounts of KSR (0.5%). Theophylline-KSR tablets also showed prolonged dissolution times, even at very low concentrations of KSR. The disintegration times of Dic-KSR tablets were roughly close to an hour and were predominantly unaffected by varying KSR levels and only marginally influenced by compression pressures. It is possible to draw the conclusion that different drugs or excipients have different minimum KSR requirements to resist compacts' disintegration process. Compounds that demonstrate low solubility in water can result in extended disintegration times for KSR compacts. The melting points of these compounds, in conjunction with the Py values of the compacts and their compaction properties, could affect the disintegration process, although a precise evaluation is necessary., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The existence of an efficient inducible transgene expression system is a valuable tool in recombinant protein production. The synthetic theophylline-responsive riboswitch (theo.RS) can be replaced in the 5[Formula: see text] untranslated region of an mRNA and control the translation of downstream gene in chloroplasts in response to the binding with a ligand molecule, theophylline. One of the drawbacks associated with the efficiency of the theo.RS is the leak in the RS structure allowing undesired background translation when the switch is expected to be off. The purpose of this study was to detect the factors causing the leak of the theo.RS in the off mode, using molecular dynamics (MD) simulations the appropriate balancing of the simulation system, using the necessary commands, a 40[Formula: see text]ns simulation was conducted. Analysis of the solvent-accessible surface area for both ribosome-binding site (RBS) regions indicated that nucleotide 79 of the theo.RS, a guanine, had the highest surface exposure to ribosome access. These results were verified with the study of hydrogen bonding of RBS regions with the RNA structure. Therefore, redesigning the RBS regions and avoiding the unmasked nucleotide(s) in the structure may improve the tightness of theo.RS in off mode resulting in the efficient inhibition of translation.

The release of the model drug theophylline from silica-pectin aerogels was investigated. The composite aerogels were prepared via impregnation of pectin alcogels with silica sol, followed by in situ silica gelation and drying with supercritical CO 2 . The structural and physico-chemical properties of the aerogels were tuned via the preparation conditions (type of silica sol, calcium crosslinking of pectin or not). Theophylline was loaded via impregnation and its release into simulated gastric fluid was studied during 1 h followed by release into simulated intestinal fluid. The swelling, mass loss and theophylline release behavior of the composites were analyzed and correlated with material properties. It followed that only aerogels prepared with calcium-crosslinked pectin and polyethoxydisiloxane were stable in aqueous systems, exhibiting a slow theophylline release governed by near-Fickian diffusion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Fertility is a result of a synergy among the sperm's various functions including capacitation, motility, chemotaxis, acrosome reaction, and, finally, the fertilization of the oocyte. Subpar motility is the most common cause of infertility in males. Cyclic adenosine monophosphate (cAMP) signalling underlies motility and is depleted by the phosphodiesterases (PDEs) in sperm, such as PDE10A, PDE1, and PDE4. Therefore, the PDE inhibitor (PDEI) category of fertility drugs aim to enhance motility in assisted reproduction technologies (ARTs) through inhibition of PDEs, though they might have adverse effects on other physiological variables. For example, the popular drug pentoxifylline (PTX), widely used in ARTs, improves motility but causes premature acrosome reaction and exerts toxicity on the fertilized oocyte. Another xanthine-derived drug, theophylline (TP), has been repurposed for treating infertility, but its mechanism of PDE inhibition remains unexplored. Here, using biophysical and computational approaches, we identified that TP binds to the same binding pocket as PTX with higher affinity than PTX. We also found that PTX and TP co-bind to the same binding pocket, but at different sites., Competing Interests: Declaration of competing interest The Authors declare that there are no competing interests associated with the manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Candida species undeniably rank as the most prevalent opportunistic human fungal pathogens worldwide, with Candida albicans as the predominant representative. However, the emergence of non-albicans Candida species (NACs) has marked a significant shift, accompanied by rising incidence rates and concerning trends of antifungal resistance. The search for new strategies to combat antifungal-resistant Candida strains is of paramount importance. Recently, our research group reported the anti-Candida activity of a coordination compound containing copper(II) complexed with theophylline (theo) and 1,10-phenanthroline (phen), known as "CTP" - Cu(theo) 2 phen(H 2 O).5H 2 O. In the present work, we investigated the mechanisms of action of CTP against six medically relevant, antifungal-resistant NACs, including C. auris, C. glabrata, C. haemulonii, C. krusei, C. parapsilosis and C. tropicalis. CTP demonstrated significant efficacy in inhibiting mitochondrial dehydrogenases, leading to heightened intracellular reactive oxygen species production. CTP treatment resulted in substantial damage to the plasma membrane, as evidenced by the passive incorporation of propidium iodide, and induced DNA fragmentation as revealed by the TUNEL assay. Scanning electron microscopy images of post-CTP treatment NACs further illustrated profound alterations in the fungal surface morphology, including invaginations, cavitations and lysis. These surface modifications significantly impacted the ability of Candida cells to adhere to a polystyrene surface and to form robust biofilm structures. Moreover, CTP was effective in disassembling mature biofilms formed by these NACs. In conclusion, CTP represents a promising avenue for the development of novel antifungals with innovative mechanisms of action against clinically relevant NACs that are resistant to antifungals commonly used in clinical settings., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Molecular interactions between active pharmaceutical ingredients (APIs) and xanthine (XAT) derivatives were analyzed using singular value decomposition (SVD). XAT derivatives were mixed with equimolar amounts of ibuprofen (IBP) and diclofenac (DCF), and their dissolution behaviors were measured using high-performance liquid chromatography. The solubility of IBP decreased in mixtures with caffeine (CFN) and theophylline (TPH), whereas that of DCF increased in mixtures with CFN and TPH. No significant differences were observed between the mixtures of theobromine (TBR) or XAT with IBP and DCF. Mixtures with various molar ratios were analyzed using differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared spectroscopy to further explore these interactions. The results were subjected to SVD. This analysis provides valuable insights into the differences in interaction strength and predicted interaction sites between XAT derivatives and APIs based on the combinations that form mixtures. The results also showed the impact of the XAT derivatives on the dissolution behavior of IBP and DCF. Although IBP and DCF were found to form intermolecular interactions with CFN and TPH, these effects resulted in a reduction of the solubility of IBP and an increase in the solubility of DCF. The current approach has the potential to predict various interactions that may occur in different combinations, thereby contributing to a better understanding of the impact of health supplements on pharmaceuticals.

A commercially available dielectric barrier discharge ionization (DBDI) source was tested with supercritical fluid chromatography-mass spectrometry (SFC-MS). The compound mixture investigated comprised caffeine, theobromine, theophylline, uracil, testosterone, and pyrene, diluted in methanol. Dynamic response ranges were evaluated with multiple injections at different concentrations. Precision studies demonstrated the robustness and sensitivity of the ionization source across a concentration range of 10-1000 ng/mL. Results from this experiment showed linear regression of 0.99 or greater for all analytes tested over the range with a relative standard deviation (RSD) of less than 10% down to 10 ng/mL for all analytes except theobromine, which had an RSD of less than 10% down to 25 ng/mL. Notably, this study marks the first investigation of sensitivity for coupling a commercial DBDI source with SFC; a limit of detection less than 1 ng/mL was achieved for all compounds. This study demonstrates chromatographic separation by SFC and MS analysis for compounds that ionize poorly using traditional atmospheric pressure ionization, such as polycyclic aromatic hydrocarbons. Combining SFC with the DBDI source opens promising avenues for analyzing compounds that were previously challenging to characterize with standard atmospheric pressure ionization techniques., (© 2024 Wiley‐VCH GmbH.)

Semisolid extrusion (SSE) 3D printing (3DP) technology is emerging due to its simplicity and potential for on-site manufacturing of personalized drug products with tailored functionality (dose, release profile), as well as recognizability (size, shape, color). However, even a minor change in the composition of the ink (the feedstock material) and the printing process parameters can largely influence the outcome of printing. This paper summarizes the recent SSE 3DP studies, where the important factors affecting the quality of the printed drug products are discussed. Further challenges are showcased by introducing a case study focusing on the design of oral theophylline immediate-release drug products. The identified crucial factors, such as the printing hardware and connected software, printing parameters, and composition of the ink are discussed. Especially, the rheological properties of the ink during the printing process, together with solidification, mechanical properties, and morphology studies of already printed products are deliberated to gain more understanding of the printability of drug products by SSE. This work aims to provide an overview of design aspects related to SSE-based fabrication of personalized drug products., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The traditional delivery of metronidazole and theophylline presents challenges like bitter taste, variable absorption, and side effects. However, gel-based systems offer advantages including enhanced targeted drug delivery, minimized side effects, and improved patient compliance, effectively addressing these challenges. Consequently, a cost-effective synthesis of N-hydroxyalkanamide gelators with varying alkyl chain lengths was achieved in a single-step reaction procedure. These gelators formed self-assembled aggregates in DMSO/water solvent system, resulting in organo/hydrogels at a minimum gelation concentration of 1.5 % w/v. Subsequently, metronidazole and theophylline were encapsulated within the gel core and released through gel-to-sol transition triggered by pH variation at 37 °C, while maintaining the structural-activity relationship. UV-vis spectroscopy was employed to observe the drug release behavior. Furthermore, in vitro cytotoxicity assays revealed cytotoxic effects against A549 lung adenocarcinoma cells, indicating anti-proliferative activity against human lung cancer cells. Specifically, the gel containing theophylline (16HAD+Th) exhibited cytotoxicity on cancerous A549 cells with IC 50 values of 19.23±0.6 μg/mL, followed by the gel containing metronidazole (16HAD+Mz) with IC 50 values of 23.75±0.7 μg/mL. Moreover, the system demonstrated comparable antibacterial activity against both gram-negative (E. coli) and gram-positive bacteria (S. aureus)., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging is a powerful tool to visualize the distribution of components, and it has been used to analyze drug release from tablets. In this work, ATR-FTIR spectroscopic imaging was applied for observing the dissolution of molecular crystals from tablet compacts. The IR spectra provided chemically specific information about the transformation of crystal structures during the dissolution experiments. Theophylline (TPL) anhydrate and its cocrystals were used as model systems of molecular crystals. The IR spectra during the dissolution of TPL revealed information about the crystal structure of TPL, which transformed from anhydrate to monohydrate in water. During a dissolution test of a model cocrystal system, it was suggested that an active pharmaceutical ingredient (API) and a coformer were dissolved in water simultaneously. The IR spectra that were acquired during the dissolution of a cocrystal tablet showed new spectral bands attributed to the API after 5 min. This suggested that the precipitation of API was observed during the dissolution experiment. Measurements from ATR-FTIR spectroscopic imaging can visualize the drug release from the tablet and determine the transformation of molecular crystals during their dissolution. These results will have an impact on clarifying the dissolution mechanism of molecular crystals.

The application of three-dimensional printing (3DP) in the pharmaceutical industry brings a broad spectrum of benefits to patients by addressing individual needs and improve treatment success. This study investigates the sustained release properties of 3DP tablets containing Theophylline (TPH), which is commonly used to treat respiratory diseases and recently having a comeback due to its potential in the treatment of conditions like Covid-19. Since TPH is a narrow therapeutic window (NTW) drug with serious side effects in the event of overdose, the release properties must be observed particularly closely. We employed a state-of-the-art single screw extrusion 3D printer, which is fed with granules containing the drug. By employing a Taguchi orthogonal array design of experiments (DOE), tablet design parameters and factor related process stability were sought to be evaluated fundamentally. Following this, examinations regarding tailored TPH dosages were undertaken and a relationship between the real printed dose of selected tablet designs and their sustained drug release was established. The release profiles were analyzed using different mathematical model fits and compared in terms of mean dissolution times (MDT). Finally, in-vivo/in-vitro correlation (IVIVC) and physiologically based pharmacokinetic (PBPK) modeling showed that a paradigm patient group could be covered with the dosage forms produced., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Here we report two novel synthetic riboswitches that respond to ASP2905 and theophylline and function in reconstituted cell-free protein synthesis (CFPS) system. We encapsulated the CFPS system as well as DNA-templated encoding reporter genes regulated by these orthogonal riboswitches inside liposomes, and achieved switchable and orthogonal control over gene expression by external stimulation with the cognate ligands.

Studying RNA-ligand interactions and quantifying their binding thermodynamics and kinetics are of particular relevance in the field of drug discovery. Here, we combined biochemical binding assays and accelerated molecular simulations to investigate ligand binding and dissociation in RNA using the theophylline-binding RNA as a model system. All-atom simulations using a Ligand Gaussian accelerated Molecular Dynamics method (LiGaMD) have captured repetitive binding and dissociation of theophylline and caffeine to RNA. Theophylline's binding free energy and kinetic rate constants align with our experimental data, while caffeine's binding affinity is over 10,000 times weaker, and its kinetics could not be determined. LiGaMD simulations allowed us to identify distinct low-energy conformations and multiple ligand binding pathways to RNA. Simulations revealed a "conformational selection" mechanism for ligand binding to the flexible RNA aptamer, which provides important mechanistic insights into ligand binding to the theophylline-binding model. Our findings suggest that compound docking using a structural ensemble of representative RNA conformations would be necessary for structure-based drug design of flexible RNA.

1-Methylxanthine is a high-value derivative of caffeine of limited natural availability with many potential pharmaceutical applications. Unfortunately, production of 1-methylxanthine through purely chemical methods of synthesis are unfavorable due to lengthy chemical processes and the requirement of hazardous chemicals, ultimately resulting in low yields. Here, we describe a novel biosynthetic process for the production of 1-methylxanthine from theophylline using engineered Escherichia coli whole-cell biocatalysts and reaction optimization. When scaled-up to 1590 mL, the simple biocatalytic reaction produced approximately 1188 mg 1-methylxanthine from 1444 mg theophylline, constituting gram-scale production of 1-methylxanthine in as little as 3 hours. Following HPLC purification and solvent evaporation, 1163 mg of dried 1-methylxanthine powder was collected, resulting in a 97.9 wt% product recovery at a purity of 97.8%. This is the first report of a biocatalytic process designed specifically for the production and purification of the high-value biochemical 1-methylxanthine from theophylline. This process is also the most robust methylxanthine N-demethylation process featuring engineered E. coli to date, capable of gram-scale production., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Meredith B Mock reports financial support was provided by US Department of Education. Ryan Summers has patent Bacterial N-Demethylases as Biocatalysts for the Production of Methylxanthines pending to United States Patent Office., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: To investigate the production and physical stability of coamorphous materials (CAM) of naringenin (NAR) and coformers-caffeine, theophylline or theobromine (CAF/THY/THE, respectively). We independently assessed the impact of moisture and temperature on the physical stability of CAMs, and transformation products after destabilization were examined., Methods: Neat grinding, liquid assisted grinding and water slurry were selected to prepare multi-component materials with NAR and CAF, THY or THE. The physical stability of CAMs was investigated at 65°C/<10%RH, 21°C/85% RH and 21°C/<10% RH. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were employed to monitor for recrystallization during the stability studies. Glass forming ability of amorphous NAR was assessed to understand CAM formation and physical stability., Results: NAR:THY and NAR:THE CAMs showed physical stability for approximately nine months, under 21°C/<10% RH while NAR:CAF CAMs destabilized in 2.5 weeks. All CAMs recrystallized within a week at 65°C/<10%RH, and the physical stability at 21°C/85% RH was in the order of - NAR:THY > NAR:THE > NAR:CAF. NAR:THY produced 1:1 cocrystal under all storage conditions, while NAR:CAF destabilized to a 1:1 cocrystal at high RH but a physical mixture at high temperature. NAR:THE was found to recrystallize as a physical mixture in all conditions. NAR was found to be strong glass, with moderate kinetic fragility and good glass forming ability., Conclusion: Five naringenin-based multi-component solids were generated in this study: 3 new CAMs, 1 new cocrystal, and 1 previously reported cocrystal. Destabilization of CAMs was found to be exposure specific and coformer dependent., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We recently reported that some adenosine binding aptamers can also bind caffeine and theophylline with around 20-fold lower affinities. This discovery led to the current work to examine the cross-binding of adenosine to theophylline aptamers. For the DNA aptamer for theophylline, cross-binding to adenosine was observed, and the affinity was 18 to 38-fold lower for adenosine based on assays using isothermal titration calorimetry and ThT fluorescence spectroscopy. The binding complexes were characterized using NMR spectroscopy, and both adenosine and theophylline showed an overall similar binding structure to the DNA theophylline aptamer, although small differences were also observed. In contrast, the RNA aptamer did not show binding to adenosine, although both aptamers have very similar relative selectivity for various methylxanthines including caffeine. After a negative selection, a few new aptamers with completely different primary sequences for theophylline were obtained and they did not show binding to adenosine. Thus, there are many ways for aptamers to bind theophylline and some can have cross-binding to adenosine. In biology, theophylline, caffeine, and adenosine can bind to the same protein receptors to regulate sleep, and their binding to the same DNA motifs may suggest an early role of nucleic acids in similar regulatory functions., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Theophylline (THP) is an emerging drug for chronic obstructive pulmonary disease whose side effects can be greatly affected by caffeine-containing real foods. Because an overdose of this substance can cause respiratory and neurological damage, producing a fast and accurate analytical procedure is critical. Based on a cutting-edge hybrid nanocomposite, this study was used to construct an electrochemical sensor for the accurate detection of THP. Spectroscopy and morphological investigation supported the easy synthesis of tetragonal-LaVO 4 (t-LV) nanopellets and LV@CNF hybrid nanocomposite. To detect THP, a highly dispersed LV@CNF nanocomposite was modified on a glassy carbon electrode as a sensing substrate. By amperometric technique, the sensor shows a wide linear range of 0.01-1070 μM, low limit of detection (2.63 nM), and sensitivity (0.228 μA μM -1 cm -2 ). Finally, the current technique was successfully used to identify THP in real food samples (chocolate, coffee and black tea)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Deoxyribonucleic acid (DNA) is a significant target for small organic and inorganic drug molecules. Understanding the DNA interaction mechanism of these molecules is vital for new drug designs. In this work, interactions between xanthine (XT), theophylline (TP), and theobromine (TB) with calf-thymus double-strained DNA (dsDNA) were monitored via an experimental and theoretical approach. Experimentally, cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques were used on the surface of the NiO/MWCNT/NNaM/PGE electrochemical platform in vitro. Kinetic parameters, including diffusion coefficients, surface concentrations, and standard heterogeneous rate constants, were measured in the absence and presence of DNA using scan rate studies. In the presence of DNA, kinetic parameters were observed to be reduced significantly. Thermodynamic parameters, such as DNA binding constants and standard free Gibbs energies, were calculated for each molecule using the CV and DPV techniques. Both techniques suggested a binding affinity order of XT > TB > TP. Theoretically, density functional theory was applied for geometry optimization, natural bond orbital analyses, and molecular orbital energies of XT, TP, and TB. Experimental and theoretical binding affinities confirm each other. The most energetically stable ligand-DNA complexes expressed that XT, TP, and TB interact with dsDNA via minor groove binding mode, using mostly hydrogen bonds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson's disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A 2A receptor antagonism and antioxidant activity, respectively. Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA. These purine derivatives can promote neuronal cysteine uptake through excitatory amino acid carrier protein 1 (EAAC1) to increase neuronal glutathione (GSH) levels in the brain. This review summarizes the GSH-mediated neuroprotective effects of purine derivatives. Considering the fact that GSH depletion is a manifestation in the brains of AD and PD patients, administration of purine derivatives may be a new therapeutic approach to prevent or delay the onset of these neurodegenerative diseases.

Designing co-crystals can be considered as a commonly used strategy to improve the bioavailability of many low molecular weight drug candidates. The present study has revealed the existence of three pseudo polymorphic forms of theophylline-citric acid (TP-CA) co-crystal obtained via different routes of synthesis. These forms are characterized by different degrees of stability in relation with the strength of intermolecular forces responsible for the co-crystalline cohesion. Combining low- and high-frequency Raman investigations made it possible to identify anhydrous and hydrate forms of theophylline-citric acid co-crystals depending on the preparation method. It was shown that the easiest form to synthesize (form 1'), by milling one hydrate with an anhydrous reactant, is very metastable, and transforms into the anhydrous form 1 upon heating or into the hydrated form 2 when it is exposed to humidity. Raman investigations performed in situ during the co-crystallization of forms 1 and 2 have shown that two different types of H-bonding ensure the co-crystalline cohesion depending on the presence of water. In the hydrated form 2, the cohesive forces are related to strong O-H … O H-bonds between water molecules and the reactants. In the anhydrous form 1, the co-crystalline cohesion is ensured by very weak H-bonds between the two anhydrous reactants, interpreted as corresponding to π-H-bonding. The very weak strength of the cohesive forces in form 1 explains the difficulty to directly synthesize the anhydrous co-crystal.

Natural rubber (NR)'s value has become increasingly important for human applications. This study prepared NR beads as floating drug delivery system by dripping NR latex into hardening solution to obtain spherical beads. Theophylline was loaded as a model drug. NR latex formed into harden beads suddenly after dripping droplets in acidic medium. These NR beads floated instantly and buoyant in HCl buffer for over 8 h with prolonged theophylline release. Their morphologies, crystallinity and thermal properties were observed using microscope, X-ray diffractometer, and thermogravimetry, respectively. Addition of 100 phr sodium bicarbonate increased drug release owing to liberation of carbon dioxide promoting porous NR matrix. Composite of 50 and 200 phr shellac in NR beads floated in HCl buffer for over 12 h. Moreover, 200 phr shellac efficiently retarded release of theophylline from NR composite beads (lower than 10 % in 8 h), whereby promoting theophylline release in phosphate buffer (pH 6.8) (approximately 80 % in 8 h). NR-shellac beads had greater water sorption (2.5 times) and erosion (4.9 times) in phosphate buffer than in HCl buffer. Thus, NR beads exhibited desirable attributes as floating drug delivery system. Both sodium bicarbonate and shellac modified matrix properties and drug release of NR beads., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To explore the feasibility of preparing different doses of tablets for personalized treatment by fused deposition modeling (FDM) 3D printing technology, and to evaluate the in vitro quality of the FDM 3D printed tablets., Methods: Three different sizes of hollow tablets were prepared by fused deposition modeling 3D printing technology with polyvinyl alcohol (PVA) filaments. Theophylline was chosen as the model drug. In the study, 20 mg, 50 mg and 100 mg of theophylline was filled into the cavity of the tablets, respectively. The microscopic morphology of the tablets was observed by scanning electron microscopy (SEM). The weight variation of the tablets was investigated by weighing method. The hardness of the tablets was measured by tablet hardness tester. The contents of the drugs in the tablets were determined by ultraviolet and visible spectrophotometry (UV-Vis), and the dissolution apparatus was used to assay the in vitro drug release of the tablets., Results: The prepared FDM 3D printed tablets were all in good shape without printing defects. And there was no leakage phenomenon. The diameter and thickness of the tablets were consistent with the design. The layers were tightly connected, and the fine structure of the formulation could be clearly observed without printing defects by scanning electron microscopy. The average weight of the three sizes of tablets was (150.5±2.3) mg, (293.6±2.6) mg and (456.2±5.6) mg, respectively. The weight variation of the three sizes of tablets were boss less than 5%, which met the requirements; The hardness of the tablets all exceeded 200 N; The contents of theophylline in the three tablets were 98.0%, 97.2% and 97.9% of the dosage (20 mg, 50 mg and 100 mg), and the relative standard deviation (RSD) was 1.06%, 1.15% and 0.63% respectively; The time for 80% drug released from the three dosage of tablets was within 30 min., Conclusion: Three different dosages of theophylline tablets were successfully prepared by FDM 3D printing technology in this study. The exploration may bring beneficial for the preparation of personalized dose preparations. We expect that with the development of 3D printing technology, FDM 3D printed personalized tablets can be used in the clinic as soon as possible to provide personalized treatment for patients.

There is growing interest in therapeutic intervention that targets disease-relevant RNAs using small molecules. While there have been some successes in RNA-targeted small-molecule discovery, a deeper understanding of structure-activity relationships in pursuing these targets has remained elusive. One of the best-studied tertiary-structured RNAs is the theophylline aptamer, which binds theophylline with high affinity and selectivity. Although not a drug target, this aptamer has had many applications, especially pertaining to genetic control circuits. Heretofore, no compound has been shown to bind the theophylline aptamer with greater affinity than theophylline itself. However, by carrying out a high-throughput screen of low-molecular-weight compounds, several unique hits were identified that are chemically distinct from theophylline and bind with up to 340-fold greater affinity. Multiple atomic-resolution X-ray crystal structures were determined to investigate the binding mode of theophylline and four of the best hits. These structures reveal both the rigidity of the theophylline aptamer binding pocket and the opportunity for other ligands to bind more tightly in this pocket by forming additional hydrogen-bonding interactions. These results give encouragement that the same approaches to drug discovery that have been applied so successfully to proteins can also be applied to RNAs.

Caffeine is a naturally occurring alkaloid and it is metabolized to paraxanthine, theophylline and theobromine. Analysis of caffeine and its metabolites is challenging since the metabolites theophylline and paraxanthine generate similar product and precursor ions. In this study, a new method was developed for the simultaneous analysis of caffeine, paraxanthine, theobromine and theophylline in horse urine using gas chromatography-mass spectrometry (GC-MS). Urine samples were treated using solid-phase extraction followed by the elution with dichloromethane-isopropanol (90:10) after the pH was adjusted to 6, and then derivatization with N-methyl-N-trimethylsilyl-trifluoroacetamide-1% trimethylchlorosilane before analysis with GC-MS. Sample preparation and derivatization steps were optimized and the method permitted elution all of these analytes within 13 min. The method was fully validated according to Commission Decision, 2002/657/EC guidelines. The calibration curves were linear with a correlation coefficient of >0.99. Precision and accuracy were well within the 15% acceptance range and the method was robust. The validation results demonstrated that the method is highly reproducible, easily applicable and selective. The method was applied to urine samples collected from racehorses to demonstrate its applicability., (© 2022 John Wiley & Sons Ltd.)

Since the report of the RNA aptamer for theophylline, theophylline has become a key molecule in chemical biology for designing RNA switches and riboswitches. In addition, theophylline is an important drug for treating airway diseases including asthma. The classic RNA aptamer with excellent selectivity for theophylline has been used to design biosensors, although DNA aptamers are more desirable for stability and cost considerations. In this work, we selected DNA aptamers for theophylline, and all the top sequences shared the same binding motifs. Binding was confirmed using isothermal titration calorimetry and a nuclease digestion assay, showing a dissociation constant ( K d ) around 0.5 μM theophylline. The Theo2201 aptamer can be truncated down to 23-mer while still has a K d of 9.8 μM. The selectivity for theophylline over caffeine is around 250,000-fold based on a strand-displacement assay, which was more than 20-fold higher compared to the classic RNA aptamer. For other tested analogs, the DNA aptamer also showed better selectivity. Using the structure-switching aptamer sensor design method, a detection limit of 17 nM theophylline was achieved in the selection buffer, and a detection limit of 31 nM was obtained in 10% serum.

In this study, a square wave voltammetric method for determination of theophylline in tablet formulation based on EDTA salt modified carbon paste electrode is presented. CV, FT-IR, and EIS results confirmed modification of the carbon paste with EDTA salt. In contrast to the unmodified carbon paste electrode, the modified carbon paste electrode showed irreversible oxidation of theophylline with considerable current enhancement. Investigation of the effect of scan rate on the Ip and Ep response of the modified electrode for theophylline revealed predominantly diffusion controlled oxidation kinetics. Under the optimized conditions, square wave oxidative peak current of theophylline in pH 7.0 PBS showed linear dependence on concentration in the range 10-200 μM with determination coefficient (R2), limit of detection, and limit of quantification of 0.99782, 0.0257 μM, and 0.0857 μM, respectively. Detection of an amount of theophylline in the analyzed tablet formulation with 1.85% error from its nominal content (120 mg/tablet) confirmed the accuracy of the developed method. Spike and interference recovery results of 98.59%, and 95.7-100%, respectively validated the applicability of the developed method for determination of theophylline content in tablet samples., Competing Interests: The authors have declared that no competing interests exist.

The aptamer domain of the theophylline riboswitch was randomized to generate a library containing millions of different variants. Dual genetic selection utilizing the cat-upp fusion gene was performed for the library, which successfully led to the identification of a caffeine-specific synthetic riboswitch. When a chloramphenicol-resistance gene was expressed under control of this riboswitch, E. coli cells showed chloramphenicol resistance only in the presence of caffeine. When inserted upstream of the gfpuv or lacZ gene, the caffeine riboswitch induced the expression of green fluorescent protein or β-galactosidase in the presence of caffeine, respectively. When tested with various concentrations of caffeine, the β-galactosidase activity was proportional to the amount of caffeine, clearly indicating the caffeine-dependent gene regulation by the caffeine riboswitch., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A variety of polymer:polymer blends was used to prepare hot melt extrudates and empty capsules (bodies and caps) by injection-molding using a benchtop extruder (Babyplast). KollidonSR:inulin and Carbothane:inulin blends were investigated. The impact of the blend ratio on the water uptake and dry mass loss kinetics upon exposure to 0.1 MHCl, phosphate buffer pH6.8 and culture medium optionally inoculated with fecal samples from Inflammatory Bowel Disease (IBD) patients were studied. Hot melt extrudates were loaded with up to 60% theophylline, capsules were filled with drug powder. Increasing the inulin content led to increased water uptake and dry mass loss rates, resulting in accelerated drug release from the dosage forms, irrespective of the type of polymer blend. This can be attributed to the higher hydrophilicity/water-solubility of this polymer compared to KollidonSR and Carbothane. Interestingly, the presence of fecal samples in culture medium increased the water uptake and dry mass loss of hot melt extrudates to a certain extent, suggesting partial system degradation by bacterial enzymes. However, these phenomena did not translate into any noteworthy impact of the presence of colonic bacteria on theophylline release from the investigated extrudates or capsules. Hence, drug release can be expected to be independent of the location "small intestine vs. colon" from these dosage forms, which can be advantageous for long term release throughout the entire gastro intestinal tract., (Copyright © 2021 Elsevier B.V. All rights reserved.)

While theophylline has been extensively studied with multiple polymorphs discovered, there is still currently no conclusive structure for the metastable theophylline form III. In this present work, by combining more widely used techniques such as X-ray diffraction and thermogravimetric analysis with more emerging techniques like low-frequency Raman and terahertz time-domain spectroscopy, to analyze the structure and dynamics of a crystalline system, it was possible to provide further evidence that the form III structure has a theophylline monohydrate structure with the water molecules removed. Solid-state density functional theory simulations were paramount in proving that this proposed structure is correct and explain how vibrational modes within the crystal structures feature and govern polymorphic transitions and the metastable form III. Through the insight provided by both simulated and experimental results, it was possible to decisively conclude the elusive crystal structure of theophylline form III. It was also shown that the correct space group for theophylline monohydrate is not P 21/ n but, in fact, Pc .

Paullinia cupana Kunth., commonly named Guaraná, is a plant from Brazil used as stimulant. The aim of this study was to evaluate the potential of extracts and tannins-rich and methylxanthines-free fraction from guaraná in the anti-inflammatory and antioxidant effect in vitro. Extract 1 obtained good yields of tannins and methylxanthines and was used to identify a type-A procyanidin trimer by LC-ESI-MS. Fraction 4 was rich in tannins and absent of methylxanthines. The extracts and fraction exhibited strong capacity for scavenging DPPH radical with IC 50 between 5.88 and 42.75-µg/mL and inhibited TNF-α release by LPS-activated THP-1 cells when compared with control cells and did not present toxicity to THP-1 cells. The fraction 4, rich in tannins, was highly active, with IC 50 5.88 µg/mL by DPPH method and inhibited TNF-α release in 83.50% at 90 µg/mL. These results reinforced potential anti-inflammatory of guaraná and data for new therapeutic approaches., (Copyright © 2021. Published by Elsevier Ltd.)

In this paper, the ultrasound-assisted solvent-mediated polymorphic transformation of theophylline was explored in detail. The induction time and reconstruction time were significantly decreased by ultrasound, thereby decreasing the total transformation time and promoting the transformation process. The ultrasound-promoted efficiency of nucleation was different in three alcoholic solvents, which was difficult to explain by traditional kinetic effects. To resolve the above confusion, binding energies calculated by Density Functional Theory were applied to explore the relationship between the ultrasound-promoted efficiency of nucleation and solute-solvent interactions. Then, a possible molecular self-assembly nucleation pathway affected by ultrasound was proposed: the ultrasound could change and magnify the crucial effect of the specific sites of solute-solvent interactions in the nucleation process. Finally, the transformation kinetics with different effective ultrasonic energies was quantitatively analyzed by Avrami-Erofeev model, indicating that the dissolution element in the rate-limiting step was gradually eliminated by higher ultrasonic energy. Fortunately, the elusive crystal form V could be easily obtained by the ultrasound-assisted polymorph transformation. This proved to be a robust method to produce high purity form V of theophylline. The outcome of this study demonstrated that the proper ultrasonic irradiation had the potential to produce specific polymorphs selectively., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

This article includes the synthesis of heterocyclic azo dye of theophylline by coupling diazonium salt of 4-chloroaniline with theophylline which is, namely, 8-(1-(4-chlorophenyl)azo)theophylline (CPAT). The complexes of cobalt and nickel were prepared by reacting their ions with CPAT ligand in ethanol under 1 : 2 ratio metal-ligand. The CPAT ligand and its complexes were characterized by elemental analysis, infrared spectrometry, electronic absorption spectroscopy, molar conductivity, and magnetic moment. The cobalt and nickel complexes show octahedral geometry having general formula [M(CPAT) 2 Cl 2 ]. This article addresses the properties of CPAT dye such as photochromic properties. The CPAT dye exhibited obvious and desired changes under irradiation with visible light (405 nm), high sensitive for pH changes which refer to its ability to be analysis indicator. CPAT dye exhibited solvatochromic properties presenting red shift with polar solvent. The CPAT and its complexes show interesting antibiological activities towards Staph. aureus and E. coli bacteria and Aspergillus fungi., Competing Interests: The author declares that there are no conflicts of interest., (Copyright © 2021 Hasan Mohammed.)

Theophylline, a typical representative of active pharmaceutical ingredients, was selected to study the characteristics of experimental and theoretical solubility measured at 25 °C in a broad range of solvents, including neat, binary mixtures and ternary natural deep eutectics (NADES) prepared with choline chloride, polyols and water. There was a strong synergistic effect of organic solvents mixed with water, and among the experimentally studied binary systems, the one containing DMSO with water in unimolar proportions was found to be the most effective in theophylline dissolution. Likewise, for NADES, the addition of water (0.2 molar fraction) resulted in increased solubility compared to pure eutectics, with the highest solubilisation potential offered by the composition of choline chloride with glycerol. The ensemble of Statistica Automated Neural Networks (SANNs) developed using intermolecular interactions in pure systems has been found to be a very accurate model for solubility computations. This machine learning protocol was also applied as an extensive screening for potential solvents with higher solubility of theophylline. Such solvents were identified in all three subgroups, including neat solvents, binary mixtures and ternary NADES systems. Some methodological considerations of SANNs applications for future modelling were also provided. Although the developed protocol is focused exclusively on theophylline solubility, it also has general importance and can be used for the development of predictive models adequate for solvent screening of other compounds in a variety of systems. Formulation of such a model offers rational guidance for the selection of proper candidates as solubilisers in the designed solvents screening.

Ligand-induced activation of CRISPR/Cas9 function is achieved based on a synergic approach through the integration of the theophylline aptamer into protein-unrecognized regions of guide RNA. This design of allosteric regulation opens a new window towards the broad involvement of RNA aptamers for conditional control of CRISPR/Cas9 function.

Theophylline is long known for its anti-ageing and anti-oxidative properties. Moreover, Tyrosinase is a crucial enzyme that regulates the melanin synthetic pathway, which is involved in various physiological metabolic processes including aging. The current paper describes the synthesis of various heterocyclic systems coupled with theophylline moiety along with their tyrosinase inhibition activity in view to identify the potent nucleus. Around 19 compounds were synthesized and screened for enzyme inhibition. Based on the current study, it is suggested that compound 18 having thiosemicarbazide has strong enzyme inhibition potential. The enzyme kinetics and docking studies provide important insights into how the compound interacts with the mushroom tyrosinase active site. The work will provide clue to developing new, potent tyrosinase inhibitors for drug development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Natural polymers have been widely studied as vehicles that have gained much interest in the encapsulation and delivery of drugs and bioactive molecules. In this study, we developed starch-modified alginate nanoparticles using a green facile technique for drug delivery application. The potential of the prepared nanoparticles for controlled drug delivery applications is demonstrated using theophylline and bovine serum albumin as model drugs. The nanoparticles possessed the encapsulation efficiency of 60 to 75%. The results of in vitro drug release studies showed the pH dependent characteristics of the prepared nanoparticles. In vitro cytotoxicity test revealed the biocompatibility of the developed nanoparticles against L929 fibroblast cell lines. The in vitro cellular uptake of nanoparticles was visualized in L929 fibroblast cells using fluorescent microscopy. The preliminary investigation suggests the developed nanoparticle is a promising candidate for drug delivery application., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Detection of the solid-state forms of pharmaceutical compounds is important from the drug performance point of view. Low-frequency Raman (LFR) spectroscopy has been demonstrated to be very sensitive in detecting the different solid-state forms of pharmaceutically relevant compounds. The potential of LFR spectroscopy to probe the in situ isothermal dehydration was studied using piroxicam monohydrate (PXM) and theophylline monohydrate (TPMH) as the model drugs. The dehydration of PXM and TPMH at four different temperatures (95, 100, 105, and 110 °C and 50, 60, 70, and 80 °C, respectively) was monitored in both the low- (20-300 cm -1 ) and mid-frequency (335-1800 cm -1 ) regions of the Raman spectra. Principal component analysis and multivariate curve resolution were applied for the analysis of the Raman data. Spectral differences observed in both regions highlighted the formation of specific anhydrous forms of piroxicam and theophylline from their respective monohydrates. The formation of the anhydrous forms was detected on different timescales (approx. 2 min) between the low and mid-frequency Raman regions. This finding highlights the differing nature of the vibrations being detected between these two spectral regions. Computational simulations performed were also in agreement with the experimental results, and allowed elucidating the origin of different spectral features.

Drug delivery to lungs via pulmonary administration offers potential for the development of new drug delivery systems. Here we fabricated the etofylline (ETO) encapsulated mannose-anchored N,N,N-trimethyl chitosan nanoparticles (Mn-TMC NPs). The prominent characteristics like biocompatibility, controlled release, targeted delivery, high penetrability, enhanced physical stability, and scalability mark Mn-TMC NPs as a viable alternative to various nanoplatform technologies for effective drug delivery. Mannosylation of TMC NPs leads to the evolution of new drug delivery vehicle with gratifying characteristics, and potential benefits in efficient drug therapy. It is widely accepted that following pulmonary administration, the introduction of mannose to the surface of drug nanocarriers provide selective macrophage targeting via receptor-mediated endocytosis. The fabricated Mn-TMC NPs exhibited particle size of 223.3 nm, PDI 0.490, and ζ-potential -19.1 mV, drug-loading capacity 76.26 ± 1.2%, and encapsulation efficiency of 91.75 ± 0.88%. Sustained drug release, biodegradation studies, stability, safety, and aerodynamic behavior revealed the effectiveness of prepared nanoformulation for pulmonary administration. In addition, the in vivo pharmacokinetic studies in Wistar rat model revealed a significant improvement in therapeutic efficacy of ETO, illustrating mannosylation a promising approach for efficient therapy of airway diseases following pulmonary administration., Competing Interests: Declaration of competing interest None. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Acrolein (ACR) is found exogenously as a widespread environmental pollutant and endogenously, where it is thought to be involved as a pathogenic factor in the progression of many pathological conditions. Eliminating ACR by dietary-active substances has been found to be one potential strategy to prevent ACR-associated chronic diseases. This study first compared the scavenging ACR efficacy of four purine alkaloids, theophylline (TP), paraxanthine (PXT), theobromine (TB), and caffeine (CAF), and then, TP, CAF, and their metabolites were investigated for their ability to trap ACR in vivo . Our results indicated that TP, which possesses an -NH moiety at the N-7 position, exhibits the best ACR-trapping capacity in vitro , while CAF has a slight ability to trap ACR due to the substitutions by -CH 3 at the N-1, N-3, and N-7 positions. After oral administration of TP or CAF, the ACR adducts of TP and the metabolites of TP or CAF (e.g., mono- and di-ACR-TP, mono-ACR-1,3-DMU, and mono-ACR-1-MU) were detected in urinary samples obtained from both TP- and CAF-treated mouse groups by using ultra-performance liquid chromatography-tandem mass spectrometry. The quantification studies demonstrated that TP and its metabolites significantly trapped ACR in a dose-dependent manner in vivo . Furthermore, we also detected those ACR adducts of TP and TP/CAF's metabolites in human urine after four cups of green tea (2 g tea leaf/cup) or two cups of coffee (4 g coffee/cup) were consumed per day. Those results indicated that dietary TP or CAF has the potential capacity to scavenge ACR in vivo.

Increasing evidence has identified the unsaturated aldehyde acrolein (ACR) as the potential factor that causes deoxyribonucleic acid cross-linking and the development of chronic diseases. The objective of this study was to investigate the mechanism by which theophylline (TP) scavenges ACR for the first time. TP efficiently scavenged ACR through forming adducts, which was demonstrated in a system in which TP was incubated with ACR at different ratios for different times for liquid chromatography with tandem mass spectrometry. Then, the mono- and di-ACR-TP adducts were purified, and their structures were elucidated by high-resolution mass spectrometry and nuclear magnetic resonance analysis. We found that the ACR residue on mono-ACR-TP further trapped one more ACR and formed di-ACR-TP adducts. Furthermore, mono- and di-ACR-TP had similar time-dependent ACR-scavenging activity to TP. Finally, we demonstrated that green tea, coffee, and cocoa inhibited ACR by trapping ACR to form mono- and di-ACR-TP adducts during the incubation of green tea, coffee, and cocoa with ACR.

Theophylline is a potent bronchodilator for the treatment of asthma, bronchitis, and emphysema. Its narrow therapeutic window (20-100 μM) demands that the blood concentration of theophylline be monitored carefully, which can be achieved by aptamer capture. Thus, an understanding of what occurs when aptamers bind to theophylline is critical for identifying a high-affinity and high-specificity aptamer, which improve the sensitivity and selectivity of theophylline detection. Consequently, there is an urgent need to develop a simple, convenient, and nondestructive method to monitor conformational changes during the binding process. Here, we report the determination of the affinity of a selected aptamer and theophylline via biolayer interferometry (BLI) experiments. Additionally, using surface-enhanced Raman spectroscopy (SERS), the conformational changes on theophylline-aptamer binding were identified from differences in the SER spectra. Finally, molecular dynamics (MD) simulations were used to identify the specific conformational changes of the aptamer during the binding process. Such a combined BLI-SERS-MD method provides an in-depth understanding of the theophylline-aptamer binding processes and a comprehensive explanation for conformational changes, which helps to select, design, and modify an aptamer with high affinity and specificity. It can also be used as a scheme for the study of other aptamer-ligand interactions, which can be applied to the detection, sensing, clinical diagnosis, and treatment of diseases., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We propose a computational workflow for robust and accurate prediction of both binding poses and their affinities at early stage in designing drug candidates. Small, rigid ligands with few intramolecular degrees of freedom, for example, fragment-like molecules, have multiple binding poses, even at a single binding site, and their affinities are often close to each other. We explore various structures of ligand binding to a target through metadynamics using a small number of collective variables, followed by reweighting to obtain the atomic coordinates. After identifying each binding pose by cluster analysis, we perform alchemical free energy calculations on each structure to obtain the overall value. We applied this protocol in computing free energy of binding for the theophylline-RNA aptamer complex. Of the six (meta)stable structures found, the most favorable binding structure is consistent with the structure obtained by NMR. The overall free energy of binding reproduces the experimental values very well., (© 2020 Wiley Periodicals, Inc.)

This study aims to explore the potential of gum extracted from okra fruit (Hibiscus esculentus) in developing hydrophilic matrices for controlled drug release applications, including determination of its percolation threshold. Flurbiprofen (poorly soluble), theophylline (sparingly soluble) and metformin (freely soluble) were employed as model drugs and incorporated using direct compression into matrices containing 40% w/w of three drugs with different physicochemical properties. Atomic force microscopy was used to study the surface texture properties of developed matrices; the surfaces of the flurbiprofen-based matrices were comparatively rough most likely as a consequence of its poor compactability. Swelling studies found that the swelling rate increased as the concentration of okra gum was increased. However, for all matrices, an increase in the gum concentration resulted in decreased drug release. The estimated percolation threshold of the okra gum calculated was found in the region of ~25% v/v plus initial porosity. Knowing the percolation threshold will enable formulators to use the minimal amount of polymer for sustain release matrices thus the controlling costs and maximising the sustainable potential of okra. This study will not only assist researchers in developing effective okra gum-based extended-release matrices but also expected to contribute towards its exploration at an industrial scale., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hydrogels are peculiar soft materials formed by a 3D polymeric network surrounded by water molecules. In these systems the mechanical and the chemical energy are well balanced and an applied external stimulus (mechanical or chemical) can cause a distinctive response, where the contributions of the mechanics and the mass transport are combined to form a "poroviscoelastic" behavior. In this work the poroviscoelastic behavior of the agarose gels has been investigated, from the experimental and modeling points of view, by applications of external mechanical stimuli. The pure gel, brought in the non-equilibrium condition, showed that the combined effect of mechanical viscoelasticity and water transport were essential to reach the new equilibrium condition. Furthermore, the agarose gel loaded with a model drug, theophylline, showed that the mechanical stimulus can enhance the drug release from the system by stretching the polymeric chains, modifying the mesh size and therefore the drug diffusion coefficient., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Fast disintegrating tablets have commonly been used for fast oral drug delivery to patients with swallowing difficulties. The different characteristics of the pore structure of such formulations influence the liquid transport through the tablet and hence affect the disintegration time and the release of the drug in the body. In this work, terahertz time-domain spectroscopy and terahertz pulsed imaging were used as promising analytical techniques to quantitatively analyse the impact of the structural properties on the liquid uptake and swelling rates upon contact with the dissolution medium. Both the impact of porosity and formulation were investigated for theophylline and paracetamol based tablets. The drug substances were either formulated with functionalised calcium carbonate (FCC) with porosities of 45% and 60% or with microcrystalline cellulose (MCC) with porosities of 10% and 25%. The terahertz results reveal that the rate of liquid uptake is clearly influenced by the porosity of the tablets with a faster liquid transport observed for tablets with higher porosity, indicating that the samples exhibit structural similarity in respect to pore connectivity and pore size distribution characteristics in respect to permeability. The swelling of the FCC based tablets is fully controlled by the amount of disintegrant, whereas the liquid uptake is driven by the FCC material and the interparticle pores created during compaction. The MCC based formulations are more complex as the MCC significantly contributes to the overall tablet swelling. An increase in swelling with increasing porosity is observed in these tablets, which indicates that such formulations are performance-limited by their ability to take up liquid. Investigating the effect of the microstructure characteristics on the liquid transport and swelling kinetics is of great importance for reaching the next level of understanding of the drug delivery, and, depending on the surface nature of the pore carrier function, in turn controlling the performance of the drug mainly in respect to dissolution in the body., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, enteric coatings based exclusively on naturally occurring ingredients were reported. Alginate (Alg) and pectin (Pec) blends with or without naturally occurring glyceride, glycerol monostearate (GMS), were initially used to produce solvent-casted films. Incorporating GMS in the natural polymeric films significantly enhanced the acid-resistance properties in gastric medium. Theophylline tablets coated with Alg-Pec blends without GMS disintegrated shortly after incubation in gastric medium (pH 1.2), leading to a premature and complete release of theophylline. Interestingly, tablets coated with Alg-Pec blends that contain the natural glyceride (GMS) resisted the gastric environment for 2 h with minimal drug release (<5%) and disintegrated rapidly following introduction to the intestinal medium, allowing a fast and complete drug release. Furthermore, the coating system proved to be stable for six months under accelerated conditions. These findings are particularly appealing to nutraceutical industry as they provide the foundation to produce naturally-occurring GRAS based enteric coatings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)